Particle Micromolding Technique Holds Promise for Future Drug-Release Therapies

Author: 
Bob Michaels

In the struggle to treat cancer, scientists have increasingly turned their attention to nanotechnology. Among their efforts, researchers are experimenting with nanoparticles as a means of regulating the release of drugs to target and destroy tumors. Joining these efforts, scientists from the Massachusetts Institute of Technology (MIT; Cambridge, MA) and the Harvard-MIT Division of Health Sciences and Technology (HST; Cambridge, MA) are producing microparticles of nearly any shape that are able to store medications and then release them in the body.

Multicompartment hydrogel from HST/MIT
Multicompartment hydrogel microstructures were generated using responsive micromolds. The first gel (top left) was molded at a low temperature, and then the second gel (top right) was patterned around the first gel at a higher temperature. The merged compartments are shown in the bottom boxes.

Previous forays into the fabrication of drug-delivering particles have relied on photolithography. The researchers’ technique, however, can be used only with certain materials, such as polyethylene glycol, and the ultraviolet light used during the photolithography process can harm cells. To overcome this obstacle, MIT PhD student Halil Tekin, HST associate professor of medicine Ali Khademhosseini, and MIT professor Robert Langer have developed a method for pouring a polymer onto a surface and then molding it into little particles. “Our drug-delivery technique is based on the general concept that you can use micro- and nanoscale molds to make particles,” Khademhosseini explains.

The HST/MIT research team’s goal is to build dynamic structures that change the shape and size of their features in the presence of particular stimuli. “The stimulus we use is temperature,” Khademhosseini explains. “Our molds are made from a polymer that is temperature responsive, so it swells or shrinks based on temperature changes.” By exploiting this dynamic capability of the mold—that is, by changing its shape—the researchers can mold complex structures into which they can place unique kinds of materials in different regions of the molded structures.

Swelling and shrinking of the material occurs approximately at body temperature, in the range of 32° to 37°C, Khademhosseini explains. Depending on the properties of the material being processed, the temperature can be altered. But above 37°C, structures become hydrophobic and shrink; they become hydrophilic and swell below 37°C. “What we fabricate is a little particle composed of two compartments,” Khademhosseini comments. “The first compartment conforms to the original shape of the mold that has been created at one temperature, while the other has been molded after the temperature has been changed. Then, you can add more material and mold it around the particle.” The particle’s different compartments are designed to contain drugs that can follow different drug-release regimens.

The particle’s drug-release functionality relies on the polymer’s ability to encapsulate pharmaceuticals and release them in a controlled fashion. There are multiple ways in which this can happen, Khademhosseini states. Gel-like materials can potentially encapsulate hydrophilic drugs. When the gel swells, water can infuse into the material and diffuse the drug out. Alternatively, more-hydrophobic materials can encapsulate more-hydrophobic drugs or degradable materials. When the material degrades, the hydrophobic drug is released slowly.

Capable of molding either swellable hydrophilic gel-like materials or such hydrophobic polymers as polylactic and polyglycolic acid, the HST/MIT process enables the researchers to produce multiphasic particles that exhibit different properties, Khademhosseini notes. For example, one material used to form the particle could be a fast-releasing polymer that elutes the drug first, while another material could hold a drug and release it more slowly. “Thus, this technology enables you to have different types of release kinetics in the same particle because you’ve fabricated different compartments that have unique release profiles,” Khademhosseini adds.

Down the road, the HST/MIT micromolding technology could be suitable for drug-delivery therapies that are injected into cancerous tumors or the circulatory system, Khademhosseini says. This technology could also be used in noncancer therapies in which drugs are administered through the digestive system. “However, there are definitely technical challenges to getting this technology ready to perform drug delivery,” Khademhosseini says. “For example, the sizes of the structures we make are still on the micro- rather than the nanoscale, although much smaller structures are required before our technique will be suitable for drug-delivery systems. Nevertheless, being able to generate complex particles with unique properties that can perform different functions from different compartments will play an important role in future drug-delivery applications.”